- /<"/>// «. ANTI-TYPHOID VACCINATION. THE IMMEDIATE 
RESULTS OF THE ADMINISTRATION OF 
3600 DOSES. 
By Major F. F. Russell, 
Medical Corps, U. S. Army. [From The Johns Hopkins Hospital Bulletin, Vol. XXI, No. 228, 
March, 1910.] 
ANTI-TYPHOID VACCINATION. THE IMMEDIATE 
RESULTS OF THE ADMINISTRATION OF 
3600 DOSES.* 
By Major F. F. Russell, 
Medical Corps, U. S. Army. 
The history of anti-typhoid vaccination is short and quite 
well-known, and it will hardly be necessary to do more than 
mention a few facts. In India Haifkine had obtained a con- 
siderable measure of success in the prevention of cholera by 
means of prophylactic inoculations, and this, in connection 
with the experimental work of Pfeiffer, led Sir Almroth E. 
Wright to take up the subject of vaccination against typhoid. 
Pfeiffer had informed Wright, in the course of a conversation, 
that it was not necessary to inoculate living cultures into 
animals to produce agglutinins, but that these anti-bodies 
could also be produced by the injection of killed typhoid 
bacilli. The idea apparently presented itself as feasible to 
both Pfeiffer and Wright that other anti-bodies, sufficient in 
quantity to protect against typhoid fever, would also be 
formed in response to the inoculation of killed typhoid bacilli 
into human beings, for Wright reported his first two cases of 
immunization in human beings in 1896,1 and Pfeiffer and 
Kolle reported the result of anti-typhoid vaccination in two 
men later in the same year.2 Although this paper covers only 
two cases it is very convincing because of the completeness 
of the investigation, for not only was an increase in the agglu- 
tinins found to follow a single dose of vaccin, but also a very 
considerable increase in the bacteriolytic power of the blood 
[83] 
* Read before the Johns Hopkins Hospital Medical Society, 
December 6, 1909. [83] 
when tested according to Pfeiffer’s well-known method with 
guinea-pigs. At this time Pfeiffer suggested the use of vac- 
cin to limit the spread of epidemics, and its use in time of 
war. In January, 1897, Wright3 made a further and more 
complete contribution to the subject in which he reported the 
results of the use of anti-typhoid vaccin in 18 people. 
Although Wright was more or less indebted to both Haff- 
kine and Pfeiffer for helpful suggestions, there is no doubt 
but that to him belongs the principal credit for placing pro- 
phylactic vaccination against typhoid on a practical working 
basis. 
In 1898 he vaccinated about 4000 men of the British In- 
dian Army/ and in the years from 1899 to 1903 he furnished 
400,000 doses to the English troops in the Boer War. It is 
reported that 100,000 inoculations were made, but not very 
much has as yet been published about the results in South 
Africa, and it is improbable that we shall get any further 
statistics of value from that campaign. The only figures 
which I have been able to find5 show that 19,000 men were 
immunized and that the incidence of typhoid among them 
was only about half as much as among the untreated, and that 
the death rate was diminished about two-thirds. 
In the latter part of 1902 considerable opposition to the 
inoculations developed in the English service, and they were 
discontinued. A Commission8 was appointed to investigate 
the whole subject, and as a result the practice was reintro- 
duced into the service in October, 1904. In the meantime 
Sir A. E. Wright had severed his connection with the English 
Army, and the work was carried on by Colonel Leishraan and 
his assistant, Major Harrison, of the R. A. M. C. 
Many thousands of doses have been given since then, and 
Leishman 7 has given the results of the immunization of 5473 
cases. These men all belonged to 16 regiments which had been 
selected for a carefully-controlled investigation on a large 
scale. As each of these regiments was in turn ordered to 
service in India, a medical officer, who had been especially 
trained for this particular duty, was attached. He lectured 
to the troops on the prevention of the disease, and called for 
volunteers and immunized them. As this medical officer is always present with the regiment 
in all its Journeys, he is able to keep careful records of all 
men immunized, and to care for, and to vaccinate additional 
volunteers and recruits from time to time as opportunity 
offers. From his knowledge of typhoid fever and clinical 
laboratory methods he is enabled to make an accurate diag- 
nosis in all suspicious cases. By means of these precautions 
Colonel Leishman is able to furnish statistics which are thor- 
oughly accurate and reliable. 
83] 
TABLE. 
Inoculated, 5473. Cases of typhoid fever, 21. Deaths, 2, or per 1000 inocu- 
lated cases, .36. 
Non-inoculated, 6610. Cases of typhoid fever, 187. Deaths, 26, or per 1000 
non-inoculated cases, 3.93. 
Among 12,083 men there were 5473 inoculated, and 6610 
uninoculated. Among the former there were 21 cases of 
typhoid with two deaths, and among the latter 187 cases and 
26 deaths. Among the exposed regiments who had been in- 
oculated with the vaccin in use at present there were 3.7 cases 
per 1000 against 32.8 per 1000 among the untreated. Only 
four out of the 21 vaccinated men who subsequently developed 
typhoid had had two doses of the vaccin, and they all re- 
covered. The other 17 had received only one dose. The 
observations of this group of 12,000 men covers a period of 
over three years, and no more perfect or convincing statistics 
are needed to show the value of this method of prophylaxis. 
L841 
There are very few facts as yet on which we can base a 
statement as to the duration of the protection. The English 
statistics Just quoted show that it will last for at least three 
years, and from the army point of view, if it lasts three years 
that is long enough, for no modern war will last as long as 
that. Three years will also cover the period of service of 
hospital internes and the training period of nurses, and by 
vaccinating them you can reduce the number of cases to half 
or even less, and such a result would justify you in insisting 
upon its use among people whose vocation exposes them to 
infection. It is of course quite illogical to conclude that the 
immunity ceases with the disappearance of the specific anti- 
bodies from the blood, since agglutinins, opsonins and bac- t84] 
teriolysins all disappear after tj-phoid fever in the course of 
a few months, as a rule, and yet the immunity lasts for many 
years if not for life. We may compare the evolutions of the 
body cells after vaccination to the evolutions of troops under- 
going training during maneuvers and the real attack of 
typhoid fever to the battle of actual war. If the cells have 
been trained in organized defense and offense during the arti- 
ficial immunization with harmless vaccins, they are better 
able to mobilize promptly and properly and to suppress the 
invading organisms during the incubation period. If they 
are not successful in completely preventing the outbreak they 
are at least more apt to be victorious than untrained cells 
which are having their first struggle with the typhoid enemy. 
The results of anti-typhoid vaccination in the German 
Colonial Army in the Herero campaign in 1904 in Southwest 
Africa were also quite favorable.8 Eight thousand men were 
vaccinated according to the method of Pfeiffer and Kolle, and 
the difference in the incidence and death rates are shown by 
the following table; 
Oases. 
Deaths. 
Per thousand of strength. Unvaccinated 
98.4 
12.6 
“ “ “ Vaccinated 
50.9 
8.8 
Roughly, there were about half as many cases and only a 
quarter as many deaths among the vaccinated. 
The necessity in the army for some such procedure as vac- 
cination, and the inadequacy of other means of prevention is 
shown by the very great prevalence of this disease in modern 
wars. In the Civil War wre had 80,000 cases in the Northern 
Army. In the Eranco-Prussian War there were 73,396 cases 
and 8789 deaths among the Germans; in fact 60 per cent of 
their total mortality was due to typhoid. During the Boer 
War there were 31,000 cases and 5877 deaths. In the Spanish 
War we had 20,730 cases and 1580 deaths among 120,000 
men or one case in 5.6 men. Eighty-six per cent of all deaths 
were due to this disease. We have no data as yet with refer- 
ence to the Manchurian War. 
In the event of a war to-day there is every reason to believe 
that we could obtain much better results in prevention than in these wars, but the number of cases would still be large, 
very large, in spite of the advance of our knowledge of the 
epidemiology of this disease during the last ten years. 
[84] 
The Preparation of the Yaccin. 
It has been shown by Wassermann and Strong9 that it is 
not necessary to use a virulent or freshly isolated culture in 
making typhoid vaecins. It is necessary, however, to select 
a culture which has good binding powers and which will pro- 
duce large quantities of anti-bodies when injected into men 
and animals. The culture which we use was isolated from the 
spleen of a fatal case many years ago. It is a typical typhoid 
in every way and grows luxuriantly and agglutinates well 
with immune serum. Its virulence has not been tested lately 
but it is probably quite safe to characterize it as an avirulent 
culture. It is grown on agar slants for 18 or 20 hours, and is 
then washed off in a small quantitjq about 2 cc., of physio- 
logical salt solution. The agar tubes are of uniform size and 
sloped in a uniform way on racks built for the purpose. They 
are sowed with a uniform quantity of a broth suspension of a 
20-hour agar growth. Every effort is made to obtain two or 
three hundred agar tubes with the same amount of growth. 
They are all looked over and any which do not come up to 
the standard are discarded. It has proven in practice quite 
a simple matter to obtain a standard 20-hour growth with 
substantially no variation from month to month. The emul- 
sion is well shaken to break up clumps, and a sample is taken 
for a bacterial count and for tests of purity of the culture. 
The emulsion is then filled into large (50 cc.) tubes which 
are sealed in the flame of a blow-pipe. The sealed tubes are 
then sunk in a water bath which is furnished with an electri- 
cally-driven stirring apparatus to secure an equal temperature 
throughout. The bath is heated to 60° C., and the tubes are 
kept submerged for 75 minutes, since experiment has shown 
that it takes 15 minutes for a large quantity of material to 
reach the temperature of the bath. The bacteria are there- 
fore killed by heating to 60° C. for one hour. We have 
never succeeded in killing the cultures with certainty at lower [84] 
temperatures or shorter exposures than this. After the cul- 
tures are thus hilled, the concentrated emulsion is diluted 
up to about 15 to 20 cc. for each agar slant. The quantity 
varies somewhat as the bacterial count serves as a check, and 
may indicate that a little more or a little less salt solution to 
the tube is necessary to give a product containing 1,000,000,- 
000 bacteria to the cubic centimeter. Before the vaccin is 
put into ampullae there is added one-quarter of 1 per cent of 
tricresol as a matter of safety. 
The vaccin is administered to two animals at least, a 
mouse and a guinea-pig, before any is used on human beings. 
The experience with tetanus in India and plague in Manila, 
from contaminated vaccins, has shown that this precaution 
is necessary. yErobic and anserobic tests for sterility are also 
made on each batch of vaccin. 
[85] 
The Keeping Qualities of the Yaccin. 
Onr oldest vaccin has now been kept in the ice-box for 15 
months, and inoculations into animals and man show that it 
is just as effective as when first prepared. 
Recent Experience with Yaccin. 
The vaccination of officers and enlisted men in our army 
was begun in February of this year (1909), and up to the 
present time completed records of the vaccinations of 1400 
individuals have been collected. 
As the work of the first year was looked upon as merely 
preliminary we have attempted to collect statistics as to the 
immediate resrdts in the way of local and general reactions, 
for it was realized that any measure like this which is purely 
voluntary, must not be too unpleasant, painful or disagree- 
able, if it is to be popular. 
Each close of vaccin is followed by a local reaction which 
varies very little either with the size of the dose or with the 
idiosyncrasy of the individual. As a rule, there is a red and 
tender spot about as large as the palm of the hand at the point 
of inoculation. This begins to appear in six to eight hours, 
and reaches its full development in about 12 hours, and then gradually subsides and disappears, as a rule, in 48 to 72 hours. [ 
It happens occasionally, especially in children, that there is 
little or no local reaction, but this is rather a rare occurrence. 
Occasionally the red and swollen area may be unusually large 
and extend from the point of inoculation to the elbow or even 
half way to the wrist. The excessively severe local reactions 
are not particularly painful, and the men are able to use the 
arms for light work without discomfort; and it has never 
been necessary to make local applications to the arms, or to 
put the arm into a sling. The severe local reactions subside 
about as quickly as the average and there are fortunately not 
very many of them. The local reaction extends up the arm 
to the axillary glands in a considerable number of instances. 
The lymph nodes are slightly swollen and tender on pressure, 
and occasionally the man will call attention to them. The 
symptoms referable to the glandular swelling disappears in 
about 24 hours and are never followed by permanent enlarge- 
ment or by suppuration. 
[851 
At the seat of the inoculation a small hard bullet-like 
nodule may persist without giving rise to any symptoms for 
a week or two before it subsides. JSTo instance of the con- 
tinued presence of this nodule beyond a couple of weeks has 
come to my knowledge, and the local reaction regardless of 
its severity passes away completely and leaves no scar or mark 
of any sort to show where the vaccination has been made. 
The general reaction varies in its symptoms much more 
than the local. In children and in many adults it can be 
truly said to be absent. In its milder form it causes a transi- 
tory headache and a feeling of weariness which lasts from two 
or three hours to a day. Slightly more marked general reac- 
tions are evidenced by considerable headache and a decided 
feeling of lassitude which lasts until about noon of the fol- 
lowing day. Occasionally there are chilly sensations without 
much rise of temperature. A few men have complained of 
nausea and a very few of diarrhoea lasting for a day or part 
of a day. It is rather interesting to note the way in which 
the men themselves describe a mild reaction. So many have 
now expressed themselves in the same way that it seems proper 
to mention it here. They say “ I thought I was going to have [851 
a sore throat ” or “ a cold ” or “ an attack of the grip, but as 
it passed off quickly I realized that it was the effect of the 
vaccination.” 
The moderate reactions are characterized by a rise of tem- 
perature to 101° to 103° F. A few have had chills, and have 
had the symptoms described above in a rather more pro- 
nounced form. They constituted only a small percentage of 
the total. 
The severe reactions are those with a temperature of 103° 
F. and above. Most of these men report having had a chill 
with more or less headache, nausea, vomiting or herpes labi- 
alis; no cases of albuminuria have been reported. We have 
taken especial pains to obtain full reports of all severe reac- 
tions, as it was realized from the beginning that if many 
occurred it would interfere greatly with carrying through the 
immunization of the army, and it is consequently gratifying 
to be able to report that very few of the vaccinations have 
been followed by severe reactions. We do not yet know what 
the conditions are which bring about the moderate and severe 
general reactions. 
The fact that a man may aheady have had typhoid fever at 
some time in the past seems to increase the chances of a 
moderate or severe reaction. Up to the present (December, 
1909) we have collected records of the vaccinations of 124 
such cases and reference to the chart on this page will show an 
undoubted difference in the severity of the reactions of those 
who have had, and those who have not had, typhoid. 
The 134 cases who had previously had typhoid were ar- 
ranged in seven five-year groups in the hope that this would 
show how long the hypersensitiveness to typhoid lasted, but 
the figures are inconclusive. Apparently it lasts for 30 to 35 
years, but the number of cases is quite small, and other fac- 
tors, such as advancing age, may he equally important in giv- 
ing a high percentage of moderate and service reactions. 
Not every case of typhoid leaves the patient in this hyper- 
susceptible or anaphylactic condition, and the fact that such 
people give a higher percentage of severe reactions than indi- 
viduals who have not been sensitized by an attack of the fever 
was not appreciated until a considerable number of record 
[861 cards had been examined. The number of cases tabulated 
(124) is so large that the increased severity can hardly be a 
coincidence. Presumably it is coupled with an immunity to 
typhoid and it therefore is not to be classed with the hyper- 
susceptibility of man or animals infected with tuberculosis 
and glanders. To what extent it may indicate residual 
typhoid affections of the bile tract, urinary tract or intestines, 
is at present unknown. Previous typhoid will not, however, 
explain all of the marked reactions. 
[86] 
It is well known that the severity of typhoid varies in dif- 
ferent epidemics, and also among individuals in a single 
epidemic, and one of the causes commonly assigned for this 
TABLE. 
[851 
Cases. 
First Dose. 
Second Dose. 
Third Dose. 
None. 
Mild. 
Moderate. 
Severe. 
None. 
2 
2 
Moderate. 
Severe. 
Non'. 
Mild. 
Moderate. 
Severe. 
1204. 
No typhoid 
59.9 
31.4 
7.5 
0.9 
67.8 
>5.6 
5.3 
1.1 
77.2 
19.2 
3.0 
0.4 
124. 
Typhoid 
60.4 
25.8 
12.0 
1.6 
64.6 
03,2 
10.3 
1.7 
76.0 
19.5 
5.4 
0.0 
26 within 5 years 
50.0 
34.6 
15 3 
0.0 
78.2 
17.3 
4.3 
1.7 
71.4 
18.9 
9.5 
0.0 
33 
“ 10 “ 
57.5 
24.2 
15.1 
3. 
45.1 
41.9 
9.6 
3.3 
72.7 
22.7 
4.5 
0.0 
29 
“ 15 “ 
70.4. 
20.6 
6.8 
0. 
71.4 
21.4 
7.1 
0. 
84. 
12. 
4. 
0. 
9 
“ 20 “ 
55.5 
33.3 
11.1 
0. 
65.5 
12.5 
25. 
0. 
57.1 
42.8 
0. 
0. 
7 
“ 25 “ 
57.1 
28.5 
14.2 
0. 
50. 
50. 
0. 
0. 
75. 
25. 
0. 
0. 
4 
“ 30 “ 
100. 
0. 
0. 
0. 
100. 
0. 
0. 
0. 
75. 
25. 
0. 
0. 
5 
“ 35 “ 
40. 
20. 
20. 
20. 
60. 
0. 
20. 
20. 
50. 
50. 
0. 
0. 
individual variation in severity is the varying susceptibility, 
or better, the varying resistance of the patient, and in default 
of any better explanation it seems reasonable to believe that 
the patients who show the greater susceptibility to the vaccin 
are those who would present the least resistance to the disease 
if naturally infected with the living typhoid bacillus. 
[86] 
Examination of the blood serum after vaccination has been 
made of a large number of cases and as the results are, as a 
rule, quite similar, the exhibition of two charts, I and II, will 
suffice as an example. They are neither better nor worse than 
many others, and are offered here merely because they cover a 
greater period of time and greater number of examinations 
than any others which we have made. The men were vacci- 
nated in March, 1909, and weekly observations on the agglu- [86] 
tination and on phagocytosis have been made regularly. Xo 
curve of bactericidal power is shown for we have not yet been 
able to get any method which will give in vitro altogether 
satisfactory results over a long period. 
All agglutinations are done by the macroscopic method, and 
the serum dilutions are made with great care, and can be 
considered quite accurate. An increase in the agglutination 
is often evident on the fourth or fifth day, and by the sixth 
to eighth day a considerable increase is always noted. The 
curve shoots up rapidly to 1-10,000 and even to 1-20,000. 
Chakt I. 
The fall begins in about six weeks and continues to approach 
normal more or less slowly so that at the end of 15 months in 
my oldest case it is not evident in dilutions above 1 in 80 to 1 
in 100. In exceptional cases the curve is neither so high nor 
so long as in the chart exhibited. The curve of phagocytosis is 
equally well marked. The rise is sharp and high and the titer 
reached is usually 1-5000. It falls more rapidly than the 
agglutination curve, but even after 10 months in the oldest 
case it has not yet dropped to normal. We encountered rather 
more trouble in developing a satisfactory routine technique for this test than for the agglutinations, and our observations 
consequently do not go so far back. The opsonic index when 
obtained by ordinary methods fails completely and the dilu- 
tion method of Neufelt is therefore used. At first the capil- 
lary pipettes of Wright, and human leucocytes, were made 
use of with progressive dilutions of the serum and salt dilu- 
tion and normal serum controls. The titer of the serum is 
expressed by the highest dilution in the final mixture, which 
showed more phagocytosis than the controls. Thus the pri- 
mary serum dilution, 1 in 10, 1 in 100, would become when 
[86] 
Chabt II. 
diluted with equal volumes of leucocytes and bacterial emul- 
sion, 1 in 30, 1 in 300, etc. By this method a rapid inspection 
of the slides eliminates all the dilutions in which the phago- 
cytosis is marked, and only the controls and those slides on 
the border line remain to be counted. In the last few months 
we have adopted the JSTeufelt method in toto, since in practice 
it takes much less time and is quite simple. The leucocytes 
are obtained from guinea-pigs after aleuronat injections into 
the peritoneal cavity, and the mixture of leucocytes, serum 
and bacteria is made in small test tubes. The serum is in- [86| 
activated at 56° C. for 30 minutes and the mixture is incu- 
bated for two hours at 37°, when smears are made and stained 
with a polychrome methylene blue. 
We have found the strain of typhoid bacillus to be very im- 
portant. All our old cultures, and even many recently isolated 
ones, are phagocyted spontaneously to such an extent that little 
difference can be seen between the controls and the serum to 
be tested. After searching through all our stock cultures and 
many recent isolations we selected strains obtained by blood 
cultures in the early stages of typhoid fever which are almost 
completely resistant to spontaneous phagocytosis, and these 
strains have been transferred at infrequent intervals, and 
only one out of the several selected has since degenerated to 
the same condition as the older cultures. With a suitable 
culture of typhoid, guinea-pig leucocytes and a rather long 
period of incubation, we found no difficulty in getting regular 
and well-marked determinations of the phagocytic power of 
the serum. 
[87] 
The leucocyte count is temporarily but regularly increased 
after each dose of yaccin. The rise is often to 15,000, and 
the fall is gradual and reaches normal in about a week. 
The accompanying chart shows graphically the percentage 
of severe (103° F. or over), moderate (100° to 103° F.), mild 
(up to 100° F.) or absent general reactions in various groups. 
The total reactions recorded is 3640 of which 0.9 per cent 
were severe, 5.7 per cent moderate, 25.3 per cent mild, and 
68 per cent absent. The same number of reactions grouped 
according to doses shows the following: 
1st Dose. 
2d Dose. 
3d Dose. 
Severe 
1.0% 
1.2% 
0.3% 
Moderate .... 
7.7 
5.6 
3.1 
Mild 
30.7 
24.9 
18,7 
Absent 
60.5 
68.2 
77.8 
The reactions of those who have never had typhoid are as 
follows (1304 persons) ; 
1st Dose. 
2d Dose. 
3d Dose. 
Severe 
0.9% 
1.1% 
. 0.4% 
Moderate 
7.5 
5.3 
3.0 
Mild 
31.4 
25.6 
.19.2 
Absent 
59.9 
67.8 
77.2 The reactions among those who had had typhoid is as fol- [871 
lows (124 persons) : 
1st Dose. 
2d Dose. 
3d Dose. 
Severe 
1.6% 
1.9% 
0.0% 
Moderate 
12.0 
10.3 
5.4 
Mild 
25.8 
23.2 
19.5 
Absent 
60.4 
64.6 
75.0 
In order to learn whether we were making any progress in 
eliminating the unpleasant effects of the vaccination, the 
REACTIONS AFTER TYPHOID FEVER VACCINATION. 
first 609 cases vaccinated are compared with the last 750. 
The graphic method shows by a glance at the chart that we 
have made decided progress in this direction, and that the 
number of unpleasant reactions has been reduced considerably. 
Up to the present time applicants have been vaccinated 
without regard to age and a few people of 50 or more years 
of age have been treated, and the reactions have been tabulated 
in 10-year periods, and it is seen from the accompanying table that the percentage of cases in which the reaction is absent 
decreases with the increase in age and the percentage of mild 
reactions increases: there is no very marked difference in the 
moderate and severe reactions at different ages. On the 
whole, one may say that the younger the applicant the less 
marked the general reactions. 
1871 
The Percentage of Different Reactions at Varying Ages. 
Ox 
O 
4- 
O 
8 
to 
o 
O 
O 
05 
o 
ox 
o 
4*> 
o 
03 
O 
to 
o 
C4 
o 
o 
Age. 
8? 
4- 
i- 
Ox 
O 
05 
o 
03 
Absent. 
S 
p 
03 
CO 
03 
4- 
to 
o 
Mild. 
03 
O 
05 
o 
GO 
8 
o 
05 
o 
4*- 
8 
Moderate. 
b 
o 
CD 
8 
O 
O 
o 
o 
8 
Severe. 
4“ 
05 
05 
05 
10 
CO 
8 
Absent. 
to 
cd 
Or 
05 
lO 
05 
to 
05 
to 
to 
05 
8 
Mild. 
o 
P 
p- 
b 
o 
O 
o 
o 
O 
GO 
o 
4“ 
O 
8 
Moderate. 
8 
o 
O 
o 
8 
8 
Severe. 
CD 
Ox 
-1 
o 
03 
GO 
CO 
4** 
CO 
03 
Absent. 
4* 
Ox 
lO 
CO 
to 
to 
OX 
O 
03 
O 
Mild. 
Pi 
8 
8 
8 
8 
O 
to 
8 
Moderate. 
b 
o 
8 
O 
o 
O 
o 
8 
O 
o 
Severe. 
CD 
i- 
qx 
ox 
2bl 
Ox 
•S 
Ox 
r 
r 
; 
I 
o 
p 
CO 
o 
co 
In children both the local and general reactions are exceed- 
ingly mild and cause little or no inconvenience. 
The history of the prophylactic use of anti-typhoid yaccin 
goes back, as we have seen, to 1898, and it is in some ways a 
matter of surprise that a method which promises so much 
has been used so little. It can be said that it has scarcely 
been used outside of the English, German and American 
armies. The reasons for the failure of the method to become 
popular in civil life, especially in hospitals, institutions, and 
among gangs of laborers employed on railroads and public 
works, are worthy of some study. It will help to place the 
conditions clearly before us if we consider for a moment the 
procedure carried out on the appearance of an epidemic of 
smallpox. In that event all contacts are immediately vacci- 
nated. The newspapers call attention to the presence of the 
disease and many people seek protection at public vaccinating 
stations or at the hands of their family physicians. In addi- 
tion all children must, as a rule, be vaccinated before they can 
be admitted to school. All recruits for the army and navy are vaccinated as soon as they are sworn in. These general 
rules are of course the result of years of experience with 
smallpox, for at one time vaccination in smallpox was in 
much the same chaotic condition as vaccination against 
typhoid to-day. We are met at the very beginning in the case 
of typhoid with such statements in modern text-books as 
this;10 
[88] 
The immediate effect of the vaccination is to diminish the re- 
sistance to infection by typhoid bacilli, and if large doses have 
been given this diminished immunity may be very marked. With 
this there is a great increase in both the bactericidal and aggluti- 
nating elements in the blood. With small doses the increased 
immunity is less and persists for a shorter time. This has led 
Wright to advise the giving of two weaker injections in prefer- 
ence to one strong one. ... It is evident that it would not be 
wise to vaccinate during an epidemic as the procedure apparently 
makes the individual less resistant to infection for a time. 
It is difficult to predict to what an extent vaccination against 
typhoid fever may be used in the future. It would certainly seem 
wise to carry it out among troops who are going to infected dis- 
tricts. In epidemics it should not be used, as already noted. 
The troublesome symptoms which occur immediately after the 
injection should not he considered as a contra-indication. 
If we are to be guided by the opinion of this writer -we 
would not be able to use the method in stamping out an epi- 
demic but must confine ourselves to long-range prophylaxis. 
Another reason for the lack of appreciation of the value of 
this measure has been the idea that it produced violent reac- 
tions and gives the patient not only a very sore arm but also 
a good deal of prostration, and often headache, fever and 
chills. A report published by Flemings, of the German 
Army, is largely responsible for this. He found that 97.1 
per cent of his cases developed fever and that the average was 
38.4° C. The highest was 40.3° and the lowest 37.3° C. 
There were chills in 63.1 per cent, headache in 61.2 per 
cent, and vomiting in 19.4 per cent. Loss of appetite oc- 
curred in practically all cases. Albuminuria was present in 
two out of the 91 treated. Herpes labialis occurred in 19.4 
per cent. 
The vaccin used by Fleming was prepared according to the 
method of Pfeiffer and Kolle, and is much stronger than 188] 
ours. They obtain only 5 cc, of finished vaccin from an 
average agar slant while we get about four times as much, 
and this excessive dosage is probably responsible for the severe 
type of general reaction obtained. It is also true that many 
of the earlier vaccinations, even those carried out by Sir A. E. 
Wright, were made with quite large doses and there were, no 
doubt, a good many severe and prostrating reactions. The 
dosage in the early days was based largely on the result of 
inoculations in animals, and was to a certain extent mis- 
leading as the usual laboratory animals are not susceptible to 
the disease, and are relatively resistant to the endotoxins. 
Now that wye have found as a result of many thousand vacci- 
nations in human beings, a more suitable and sufficient dose 
we are no longer troubled to any considerable extent with the 
severe reactions. 
The greatest of all obstacles with which we have to contend, 
however, is the very prevalent idea of the negative phase: the 
idea that an individual is more apt to contract typhoid fever 
for a short time after vaccination than he would have been 
had he not been immunized. The expression “ negative 
phase ” we owe to Sir A. E. Wright, who stated that there is 
a drop in the anti-toxic and bactericidal content of the blood 
for a short period following a dose of the vaccin. He quotes 
Ehrlich and Madsen to the same effect. Eeference to his 
paper will show, however, that he was not dealing with the 
effect of the first dose, but with the effect of a dose of toxin 
on an animal already immunized. Ehrlich’s and Madsen’s 
studies were made on the effects of the administration of 
diphtheria and tetanus toxin and not with typhoid or any of 
the group of bacteria which act through insoluble or endo- 
toxins. There are good reasons for believing that behavior of 
these two groups of bacteria is quite different. Because a 
negative phase and increased susceptibility to the toxin de- 
veloped after a time in horses used for the production of diph- 
theria antitoxin, we should not infer that a period of in- 
creased susceptibility follows the injection of killed typhoid 
bacilli or any other of the bacteria which do not produce 
exotoxins.11 It does not appear that the effect was to diminish 
the quantity of protective anti-bodies below the normal, but merely somewhat below the level attained during a preceding [ 
immunization. In the same paper he gives several curves of 
the bactericidal power of the blood following anti-typhoid 
vaccination. In two of these there is shown a decided drop 
below the normal after the first vaccination, in a third there 
is a very small negative phase of bactericidal power, and in 
the fourth there is a complete suppression of the negative 
phase. Wright’s12 own conclusions as to the practical im- 
portance of the law of negative and positive phase in con- 
nection with prophylactic inoculations undertaken with living 
or sterilized vaceins are as follows: 
[88] 
In considering, in the light of individual results obtained in 
certain series of anti-typhoid inoculations undertaken in actually 
infected surroundings, the significance of the negative phase of 
bactericidal power after anti-typhoid inoculation, I have called 
attention to the fact that the success of these prophylactic in- 
oculations is imperiled where excessive doses of vaccin are 
administered to patients in actually infected surroundings, or im- 
mediately before transference to such surroundings. Basing my- 
self upon information collected in India by the Indian Plague 
Commission, in connection with Mr. Haffkine’s anti-plague vac- 
cination, I made a similar suggestion in connection with this pro- 
phylactic inoculation. And I have recently learned that the idea 
of a risk attaching to the inoculation of large doses of vaccin in 
infected surroundings suggested itself also to several observers in 
South Africa who had occasion to watch the effect of the anti- 
typhoid inoculation there undertaken. If the suggestion made by 
me in connection with anti-typhoid and anti-plague inoculation 
are justified, we may not reasonably expect to find indications of 
an increased susceptibility to smallpox in the period supervening 
immediately upon the development of vaccinia pocks. It seems to 
me that such evidence can be found. 
A final word on this question will he appropriate. If the risks 
incidental to the production of a negative phase attach, as I believe 
they do, to prophylactic inoculations in the case of all septicaemic 
diseases alike, it is obviously incumbent upon us neither to ignore 
nor to magnify these dangers, and, above all, to recognize that 
these risks can be minimized. Let it be observed that the risk of 
a negative phase comes seriously into consideration only when 
excessive doses of vaccin are employed, and when the prophy- 
lactic inoculations are undertaken in the actual presence of in- 
fection. The remedy lies at hand. It lies in the case where a 
sterilized bacterial culture is employed in the reduction of the 
dose. It lies in the case of anti-smallpox vaccination in the re- 
[89] [89] 
duction of the number of insertions; in other words, in limiting 
the elaboration of the toxins by diminishing the area of skin 
surface employed for the culture of the organism of vaccinia. 
We see that in Wright’s*opinion the negative phase is not 
necessarily associated with every immunization process but is 
due to avoidable causes, i. e., to excessive dosage. In another 
place he states that “ where a dose of vaccin which is only 
just sufficient to produce an effect on the blood is administered 
the negative phase is elided and there is registered only a 
positive phase.” 
In the preface 13 he again made the following rather char- 
acteristic statement: 
When once it had become clear in the course of an investigation 
into the effect of anti-typhoid inoculation upon the blood, that it 
would be practicable to control the “ negative phase ” and to 
confer upon a patient the advantages of immunization without 
risk or appreciable delay, the thought lay very near that it might 
prove possible to elicit even after microbes had made good their 
entry into the body, an immunizing response which would be 
therapeutically valuable. 
I might quote further, if space permitted, from Wright to 
show that while we should not ignore, neither should we mag- 
nify the danger of the negative phase. 
I would not take so much of your time in considering the 
various aspects of the negative phase had it not proven the 
greatest obstacle to our progress in immunizing the army. 
As you may know, we have very little typhoid in the service 
in time of peace. In 1908, the last year for which statistics 
are available, the admission rate was 294 per 100,000 strength, 
with a death rate of 23 against a death rate of 52.3 (1906) 
for Washington, and 34.3 (1906) for Baltimore. The death 
rate in the army is a little less than half that among the civil 
population of military age in the registration area of the 
United States. 
The time when officers and men begin to inquire about the 
benefits of vaccination is after a case or two has occurred or a 
small company epidemic has broken out. The medical officer 
is appealed to and he very probably looks up the subject and 
finds that if he proceeds to immunize the command he will be proceeding contrary to the advice of many authorities. 
After the epidemic is over and the danger past no one is then 
interested in the subject and it is dropped. 
[89] 
[89] 
It will, therefore, be worth whiBe to look upon this problem 
from another point of view, the experimental one. 
R. Pfeiffer, in 1908, summed up our knowledge of the 
negative phase as follows: 
The existence of the so-called negative phase is of considerable 
importance in the question of protective inoculation against 
typhoid. The existence of this condition was first asserted by 
Wright and said to consist in a heightened susceptibility to in- 
fection among the inoculated, which begins immediately after 
injection and lasts until the beginning of the immunity reaction. 
This negative phase of Wright’s has played a great part in the 
literature of anti-typhoid inoculation in late years, and it, more 
than anything else, is to be charged with the reluctance to take up 
the practical carrying out of inoculations in spite of the undeni- 
able results which are obtained when the practice is carried out 
in the proper way. 
It is really rather remarkable that thorough experimental work 
on this subject hardly exists. We have before us only the work 
of Wright and his students, whose method cannot be said to be 
wholly unobjectionable since it is based principally on the so- 
called opsonic effect of the serum, whose importance in the pro- 
duction of immunity is not yet really cleared up, and which, there- 
fore, is hardly sufficient grounds upon which to base such very 
important conclusions. 
In the immunization of animals to various toxins it not seldom 
occurs that as a result of the inoculation of the poison there is a 
temporary sinking in the curve which represents the variation in 
the antitoxic titer of the serum, and this has been designated as 
a negative phase; but it has been very wrongly so-called, since a 
fall below the normal strength of the serum is not observed which 
would correspond to a condition of heightened susceptibility as 
contrasted with the normal. The same criticism might be made 
of the statement of Kutscher and Hetch, that after the second 
inoculation the bacteriolytic titer of the serum fell below that 
produced by the first inoculation; finally, certain clinical observa- 
tions have been brought forward to prove the existence of the 
so-called negative phase: Men have been taken sick with an 
especially severe form of typhoid fever immediately after the in- 
oculation of an anti-typhoid vaccin. There are, however, not a 
very great number of such cases, so that in drawing conclusions 
from them a certain amount of caution is necessary. 
Theoretically the acceptance of a negative phase is an almost L891 
L891 
self-evident consequence of the well-known Ehrlich side chain 
theory. 
Really a certain number of the protective bodies present in the 
normal serum must be anchored at least temporarily in satisfying 
the receptors of the vaccin which is injected, and so cause a sink- 
ing of the bactericidal titer of the serum to appear. The only 
Question is whether this fall with the amount of the vaccin which 
is used in actual practice is sufficient to call forth a distinct in- 
ci ease in susceptibility to infection. It is known from the investi- 
gations of Pfeiffer and Friedberger that in bacteriolysis the ambo- 
ceptors which are anchored at the beginning of the process, soon 
become free and again able to combine, that is, they are cut out of 
the circuit for a short time only. On the other hand, the quantita- 
tive relations of the amount of bacterial substance which it is 
practicable to inject into a man in the shape of a vaccin to the 
anti-bodies which are normally present in the body, are not such 
as to occupy any great number of them; so that the temporary 
anchoring of a certain portion of these anti-bodies by the small 
quantity of vaccin used would be quite insignificant in comparison 
to the entire quantity of anti-bodies present in the body. This 
explanation applies even more forcibly to men who already have 
an increased immunity due to a previous inoculation when they 
are subjected to a second dose than it does to normal men. The 
questions which are here raised are suitable for experimental 
proof only to a certain degree. 
Since 1898, R. Pfeiffer and Marx have followed, by means of 
approved methods, the changes in the blood serum of rabbits 
which had received subcutaneously relatively large doses (several 
cultures) of killed cholera germs. In these experiments a fall in 
the amount of protective bodies already present in the normal 
serum has never been observed; on the contrary, there has often 
been observed even in the first 24 or 48 hours a certain, though 
small rise, which is brought about by the specific irritation acting 
on the blood-forming organs so that they begin to pour out the 
corresponding secretion. These facts have not been sufficiently 
considered by the adherents of the negative phase. Quite lately I 
have, together with Friedberger, attacked this problem. In some 
experiments which have not yet been published we have com- 
pletely convinced ourselves that guinea-pigs, which had received 
under the skin of the back relatively large doses of killed typhoid 
cultures (doses which reckoned according to the body weight 
were many hundred times the quantity of vaccin used to im- 
munize men) did not show a diminished resistance to intra peri- 
toneal infection with living typhoid bacteria, but on the contrary 
showed a distinctly increased resistance, and indeed this increase 
in resistance appeared within a few hours and was demonstrable 
[901 up to the moment when, as we know, a secretion of specific ambo- 
ceptors begins. 
L90] 
In these unequivocal experiments there was, therefore, not the 
slightest indication of a negative phase. One is reminded of the 
older experiments of R. Pfeiffer and Isaeff, which led to the con- 
ception of a condition of (non-specific) resistance as contrasted 
to a condition of true (specific) immunity. 
In our newer experiments a non-specific resistance which arises 
as a result of the injection of typhoid culture, plays the principal 
part in protecting the animal, and this is made quite clear from 
the fact that the guinea-pigs which had been treated with typhoid 
were at the same time made more resistant to infection with 
cholera and vice versa. I do not desire to apply these results 
obtained with animals, without further experimentation directly 
to mankind, but taking all these things into consideration one 
must wish before accepting the existence and the significance of 
the negative phase in mankind, that further experimental data be 
brought forward. 
Emery summarizes the work of Pfeiffer and Friedberger as 
follows: 
They conclude that the fear of a negative phase is exaggerated; 
and it must not be forgotten that the essence of the “ opsonin 
therapy ” consists in administering a dose of vaccin, in the first 
instance, while the index is low. 
There is thus no direct proof that the period of the negative 
phase is coincident with the period of hypersensitiveness to infec- 
tion. And when we compare it with the period of increased sensi- 
tiveness to toxins we find that whereas the negative phase comes 
on almost immediately, the hypersensitiveness to toxins or tuber- 
culin, or anaphylaxis to serum, takes some days to develop. 
In prophylactic vaccination against cholera we hear noth- 
ing of any increase of susceptibility following this immuniza- 
tion. Murata18 has reported its use in a very wide spread 
epidemic of the disease in Japan in 1902. There were 1299 
cases and 902 deaths, 73.3 per cent. The epidemic began on 
the 31st of July and lasted until December 23. The vacci- 
nation was begun on August 5, that is, within a few days of 
the beginning of the outbreak and during the progress of the 
epidemic 77,907 persons were vaccinated; among these there 
were only six cases per 10,000 while there were 13 or over 
twice as many among the unvaccinated. Murata does not 
even mention the negative phase in his report. L90] 
It is noteworthy that 10 years’ experience with anti-plague 
vaccination17 has shown that there is no basis in fact for the 
hypothesis suggested by Sir A. E. Wright, that a negative 
phase or period of increased susceptibility might follow the 
vaccination, and that experience has shown that individuals 
can be vaccinated on the appearance of an epidemic or at any 
time during its course, and that the vaccination not only does 
not predispose to infection, but if given during the incuba- 
tion period actually mitigates the disease. 
It is hardly necessary to do more than mention Wright’s 
views as to a negative phase after vaccination against small- 
pox to dispose of the question. The contrary view is too 
firmly established to be shaken. 
Victor Vaughan, of Ann Arbor, has informed me that his 
results have been quite similar to those of Pfeiffer, and that 
his animals are not more susceptible but more resistant to 
infection immediately after vaccination. 
Col. Leishman18 informs me that the negative phase in anti- 
typhoid vaccination is a negligible factor. 
During the last two years a considerable number of cases 
of typhoid fever have been treated with vaccins, and although 
the therapeutic value of the measure has not been determined, 
we have at least found out that it does no harm, and that 
clinically no negative phase follows the giving of vaccins. 
Since the introduction of vaccination in the army we have 
had 135 cases of typhoid among approximately 75,000 men, 
and only one of these was in a man who had been vaccinated. 
He received the first dose in Hew York and left next day for 
San Francisco. The second dose was received 10 days later 
at sea. On the 19th day after the first dose he was taken into 
hospital with typhoid. Infection probably occurred between 
the administration of the first and second doses while crossing 
the continent. He ran a mild course, the temperature 
reached 103° F. once only, and there was no relapse. One 
other case developed on the same transport in a man who had 
not been inoculated. 
With this exception there have been no cases among the 
1400 people immunized. 
The procedure has been introduced so recently that it is not yet possible to form any idea of the amount or the dura- 
tion of the immunity from statistics. 
190] 
There has been no opposition from the laity and it is felt 
that anti-typhoid vaccination in the army has successfully 
passed the introductory stage, and that its use should be 
rapidly extending among all those whose vocation exposes 
them to the possibility of typhoid infection. 
The following conclusions on this subject seem to be Justi- 
fied : 
1. Vaccination against typhoid undoubtedly protects to a 
very great extent against the disease. 
2. It is an indispensable adjunct to other prophylaxis 
among troops and others exposed to infection. 
3. It is very doubtful if there is an increase of suscepti- 
bility following inoculation. 
4. Vaccination during the disease, for therapeutic purposes, 
fails to reveal any evidence of a negative phase. 
5. The statement that vaccination should not be carried 
out in the presence of an epidemic is not justified by the facts 
at hand. 
6. The procedure is easily carried out and only exception- 
ally does it provoke severe general reactions. 
7. No untoward results have occurred in this series of 3640 
vaccinations. 
BIBLIOGRAPHY. 
1. Wright: Lancet, London, September 19, 1896. 
2. Pfeiffer and Kolle: Deutsche Med. Wochnschr., November 
12, 1896. 
3. Wright; Brit. M. J., January 30, 1897. 16. 
4. Wright: Lancet, London, September 6, 1902. 
5. McCrae, in Osier’s Modern Medicine. 1909. II. 207. 
6. Leishman, W. B.: Report on the blood changes following 
typhoid inoculation. London, 1905, Harrison & Sons. 
7. J. Roy. Army M. Corps. London, 1909. XII. 166. 
8. Mil. Surg. 1909. XXIV. 53. 
9. A. Wassermann: Ziir activen Immunisierung des Menschen. 
Festschrift fur R. Koch. 1904. 
10. McCrae, in Osier’s Modern Medicine. Yol. II, p. 207. 
11. Emery; Immunity and Specific Therapy. London, 1909. 
281. 
191] [91] 
12. Wright: Studies on Immunization. London, 1909. Or Bost. 
M. & S. J., May 9, 1903. 
13. Ibid. 
14. Pfeiffer: Centralbl. f. Bakteriol., 1908. XL. Referato 712. 
15. Emery: Immunity and Specific Therapy. London, 1909. 
281. 
16. Murata: Centralbl. f. Bakteriol., 1903-4. 1 AM. Orig. 605. 
17. Haffkine; Royal Society Epidemiological Section. Decem- 
ber 2, 1907. 
18. Personal communication.